Do you want to live a longer life in good health? Simple practices can make some difference, such
as exercise or calorie restriction. But over the long haul all that really matters is progress in medicine:
building new classes of therapy to repair and reverse the known root causes of aging. The sooner these
treatments arrive, the more lives will be saved. Find out how to help »

09

Aug

2016

Considering the Mechanisms and Treatment of Inflammaging

Today I'll link to an open access review paper on the topic of inflammaging: what it is, what is known of its mechanisms, and approaches to building treatments. The view on treatments is very mainstream and unambitious, in that it doesn't go beyond supplementation, calorie restriction mimetics, and other drugs with marginal effects, such as metformin. This is driven by a strategic approach that ignores the search for root causes in favor of evaluating the dysfunctional system as a whole and seeking to alter its operation, to force it into a mode of operation that resembles that of youth and health. This view of research and development is precisely why the mainstream is struggling to make much of an impact in the treatment of aging, and why they see the control of aging as a distant goal: trying to make a damaged machine run well without repairing the damage is a very challenging task. If we are to see progress in the treatment if aging, it will come from those researchers who aim to repair the low-level biological damage that causes aging, not merely paper over it.

That said, you may find the rest of the paper to be an interesting view of the way in which the immune system runs awry in later life. The authors here differentiate between inflammaging and immunosenescence, though I'm not convinced that these are really distinct enough to be considered two separate things given the present understanding of immune dysfunction in aging. Inflammaging is very focused on chronic inflammation, as you might imagine, while immunosenescence is focused on the declining effectiveness of the immune response. I see these as two perspectives on the same very complex phenomenon. Chronic inflammation increases with age, and contributes to all of the common age-related conditions. Becoming overweight, and thus carrying around excess visceral fat tissue, is one way to produce greater inflammation. Even if you stay in shape, however, the immune system becomes increasingly disarrayed in ways that provoke inflammation. The molecular damage of aging and a lifetime of exposure to pathogens produces an aged immune system that is both overactive and ineffective at the same time. Inflammation is a necessary part of the immune response, but if the switch is jammed in the on position, that inflammation produces a growing burden of damage to tissues and organs.

What to do about all of this? Well, not the items on the list provided in this paper, that is certain. For my money, the same general approaches to immune aging advocated in the SENS view of rejuvenation therapies should put a dent into inflammaging. These include: selectively removing immune cells that have become uselessly specialized to herpesviruses and do nothing but take up space; restoring youthful function in the thymus to increase the rate at which new immune cells are generated; supplying periodic infusions of immune cells created from the patient's own cells; and beyond that the standard SENS plan of repairing all known cell and tissue damage. Senescent cells cause inflammation, for example, and their removal is on the SENS agenda. Since senescent cell destruction is a going concern in the laboratory we should have a good view of its impact on inflammation in aging a few years from now. In the view of aging as an accumulation of damage, problems in old people that can be traced to signaling issues - differences in levels of specific proteins - are reactions to the presence of rising levels of molecular damage. Remove all of the damage and the signaling should revert to that of a young individual. This is more or less the opposite view on strategy from the systems biology perspective put forward in this paper.

A main feature of the aging process is a chronic progressive increase in the proinflammatory status, which was originally called "inflamm-aging". Inflamm-aging is the expansion of the network theory of aging and the remodeling theory of aging. The network theory of aging posits that aging is indirectly controlled by the network of cellular and molecular defense mechanisms. The remodeling theory, which was put forward to explain immunosenescence, is the gradually adaptive net result of the process of the body fighting malignant damage and is a dynamic process of optimization of the trade-off in immunity. In the process of aging, some researchers pointed out that the phenomenon where adaptive immunity declines is called immunosenescence, while the phenomenon where innate immunity is activated, coupled with the rise of proinflammation, is called inflamm-aging. Some regard the chronic inflammatory process with age as inflamm-aging, while others proposed the oxidation-inflammation theory of aging. Despite the lack of agreement on definitions and terminology, there is consensus that the primary feature of inflamm-aging is an increase in the body's proinflammatory status with advancing age.

The inflammation during inflamm-aging is not in a controlled inflammatory state. Inflammation is a series of complex response events which are caused by the host system facing a pathogen infection or various types of tissue injury. These response events are characterized by interactions between the cells and factors in the microenvironment and by regulation of the balance between physiological and pathological signaling networks. In common conditions, inflammatory responses disappear when proinflammatory factors in infection and tissue injuries are eliminated and then change into a highly active and well regulated balanced state, which is called resolving inflammation. However, in the presence of some as yet uncertain factors, such as persistent and low intensity stimulation and long-term and excessive response in target tissues, inflammation fails to move into a steady state of anti-infection and tissue injury repair; instead the inflammation continues and moves to a nonresolving inflammation state.

Inflamm-aging is a determinant of the speed of the aging process and of lifespan and is highly related to Alzheimer's disease, Parkinson's disease, acute lateral sclerosis, multiple sclerosis, atherosclerosis, heart disease, age-related macular degeneration, type II diabetes, osteoporosis and insulin resistance, cancer, and other diseases. Inflamm-aging also increases morbidity and mortality, significantly harming the health of patients, and causes a decline in the quality of life of patients. Chronic, subclinical inflammation and immune disorders coexist in the process of inflamm-aging. Epidemiological studies show that with age there is an imbalance in the loss of old bone and the formation of new bone. Inflamm-aging may be one of the contributing factors to the imbalance and to the subsequent excessive loss of bone.

Based on the essential effects and our understanding of inflammatory cytokine pathways in the process of inflamm-aging, we can begin to explore the inflammatory cytokine network and perform a quantitative evaluation of inflamm-aging. Inflammatory cytokines, including interleukins, tumor necrosis factor, and interferon, mediate their effects by binding to their receptors and competing in a complex cell-cell network. These cytokines act in both paracrine and autocrine ways to exert direct effects on the microenvironment. This plays an important regulatory role by activating inflammatory and immune cells and by releasing cytokines. Inflammatory cytokines form a complex network which extends in all directions and throughout the whole body. The inflammatory cytokine network can be divided into the proinflammatory cytokine network and anti-inflammatory cytokine network. As with the immune reaction, the inflammatory reaction is also a normal defense function. A moderate inflammatory reaction is advantageous to the body, whereas a high reaction is harmful and the outcome of these reactions is determined by changes in the inflammatory cytokine network. The dynamic balance between the proinflammatory cytokine network and the anti-inflammatory cytokine network maintains the normal function of inflammation in body. Once the balance is broken, pathological inflammation occurs. Therefore, we infer that the cause of inflamm-aging is an imbalance in the proinflammatory cytokine and anti-inflammatory cytokine networks, which leads to a proinflammatory status with increasing age. This may be the mechanism of inflamm-aging.

In summary, inflamm-aging and the inflammatory cytokine network are both classical systems biology issues. The inflammatory cytokine network is involved in the process of inflammation and senescence and may be the ideal breakthrough point of research into inflamm-aging. Omics, such as genomics, transcriptomics, proteomics, and metabolomics, are excellent methods to solve systemic biology problems. Therefore, under the guidance of systems biology, it would be novel strategy to conduct basic research into inflamm-aging using omics methods to identify characteristic inflammatory cytokine genes in the process of aging and to uncover new mechanisms to regulate inflammatory cytokines during inflamm-aging. This will also illustrate the mechanism of inflamm-aging and provide new ways to assess inflamm-aging.

Comments

Low-Grade inflammation is the hallmark of aging (Inflammaging). This condition is largely identified now as coming from the gut (intestines), the so-called microbiota comprised of trillions of cells. The gut bacteria in modern humans has been profoundly changed by processed foods, high fructose corn sugar and refined carbohydrates, which gave rise to the era of autoimmune disorders and allergies. The recent revelation that probiotics rather than probiotics (Lactobacillus acidophilus, Bifidus) exert a more demonstrative effect over gut bacteria and inflammation is yet to be fully put into practice. In a recent study the red wine molecule resveratrol, considered an anti-aging agent, altered the balance between two families of gut bacteria (bacteroidetes/firmicutes) and indirectly abolished a toxin in the liver which in turn facilitated the flow and excretion of bile (bile is made from cholesterol) that resulted in eradication of arterial plaque (atherosclerosis) in lab animals.

Posted by: Bill Sardi at August 14th, 2016 7:44 AM

I do not fully understand the comment section beginning "... indirectly abolished a toxin in the liver which in turn facilitated the flow and excretion of bile (bile is made from cholesterol) that resulted in eradication of arterial plaque (atherosclerosis) in lab animals."

Does this mean that the toxin facilitates the excretion of bile or that, by blocking the toxin, the bacteria effectively facilitated the flow?
Also does this mean that the flow of bile eradicates atherosclerosis in lab animals?

Bile acids are involved in the formation of gall stones I believe but how I do not know so I would be grateful for more information about this.

Thank you for the information

Posted by: Victor Taylor at January 26th, 2017 5:09 AM

Though I read your blog with interest David, your approach seems too far up the tree to be of use to the average person. As you say in the current piece, "If we are to see progress in the treatment of aging, it will come from those researchers who aim to repair the low-level biological damage that causes aging, not merely paper over it."
To begin at the root of life, after photosynthesis, humification is the second most important organic process on Earth. It is responsible, for example, for all fossil coal, oil, and gas deposits. Human bodies are simply a continuing form of this bacterial fermentation of the foods we eat. The 50 trillion plus biota in the human gut weigh more than the brain. All constantly digesting and fermenting, they have at least a million active genes, compared to our 25,000 genes. There's no doubt who is in control (13).
Nevertheless, as documented in my 1994 book, The New Nutrition, modern agriculture, has increasingly neglected the humus essential to soil fertility and fecundity, and has developed artificial systems to grow most produce, which are entirely lacking in most of the healthful components of the earth. The average microbiome is likely starving, certainly in a state of "low level biological damage". Recent research strongly links the current epidemics of obesity, the metabolic syndrome, adult-onset diabetes, and, yes, inflammaging, to a disrupted microbiome.
Many thousands of biotic genes control the human gut and organs. They return everything to the soil in our elimination. The human body is aptly described as a temporary, free-moving extension of the earth itself. Unless we first repair the damage at this base of human life, all the other manipulations will likely continue to fail.
Our study of aging with free-living human subjects, now in its 10th year, has struggled to solve this problem. Aided by the The Human Microbiome Project data, published by the McDonnell Genome Institute at Washington State University from 2012 on, we have since had some startling results. Our oldest subject, however, is only 89. Contact me, and I will contact you when any subject in my work or yours surpasses the lifespan of Jeanne Calment.
Refs on request.

All of Fight Aging!, with the exception of the
introductory articles, is published under the
Creative Commons Attribution 4.0 International License.
In short, this means that you are encouraged to republish and rewrite
Creative Commons licensed Fight Aging! content in any way you see fit. We
only ask that that you are polite and (a) link to the original,
(b) attribute the author, and (c) attribute Fight Aging!.